Oxidation of Protein Kinase A Regulatory Subunit PKARIα Protects Against Myocardial Ischemia-Reperfusion Injury by Inhibiting Lysosomal-Triggered Calcium Release.
calcium signaling
lysosome
protein kinase A phosphorylation
redox
reperfusion injury
Journal
Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763
Informations de publication
Date de publication:
02 02 2021
02 02 2021
Historique:
pubmed:
14
11
2020
medline:
30
12
2021
entrez:
13
11
2020
Statut:
ppublish
Résumé
Kinase oxidation is a critical signaling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, PKARIα (type-1 protein kinase A) can be reversibly oxidized, forming interprotein disulfide bonds in the holoenzyme complex. However, the effect of PKARIα disulfide formation on downstream signaling in the heart, particularly under states of oxidative stress such as ischemia and reperfusion (I/R), remains unexplored. Atrial tissue obtained from patients before and after cardiopulmonary bypass and reperfusion and left ventricular (LV) tissue from mice subjected to I/R or sham surgery were used to assess PKARIα disulfide formation by immunoblot. To determine the effect of disulfide formation on PKARIα catalytic activity and subcellular localization, live-cell fluorescence imaging and stimulated emission depletion super-resolution microscopy were performed in In both humans and mice, myocardial PKARIα disulfide formation was found to be significantly increased (2-fold in humans, Disulfide modification targets PKARIα to the lysosome, where it acts as a gatekeeper for two-pore channel-mediated triggering of global calcium release. In the postischemic heart, this regulatory mechanism is critical for protection from extensive injury and offers a novel target for the design of cardioprotective therapeutics.
Sections du résumé
BACKGROUND
Kinase oxidation is a critical signaling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, PKARIα (type-1 protein kinase A) can be reversibly oxidized, forming interprotein disulfide bonds in the holoenzyme complex. However, the effect of PKARIα disulfide formation on downstream signaling in the heart, particularly under states of oxidative stress such as ischemia and reperfusion (I/R), remains unexplored.
METHODS
Atrial tissue obtained from patients before and after cardiopulmonary bypass and reperfusion and left ventricular (LV) tissue from mice subjected to I/R or sham surgery were used to assess PKARIα disulfide formation by immunoblot. To determine the effect of disulfide formation on PKARIα catalytic activity and subcellular localization, live-cell fluorescence imaging and stimulated emission depletion super-resolution microscopy were performed in
RESULTS
In both humans and mice, myocardial PKARIα disulfide formation was found to be significantly increased (2-fold in humans,
CONCLUSIONS
Disulfide modification targets PKARIα to the lysosome, where it acts as a gatekeeper for two-pore channel-mediated triggering of global calcium release. In the postischemic heart, this regulatory mechanism is critical for protection from extensive injury and offers a novel target for the design of cardioprotective therapeutics.
Identifiants
pubmed: 33185461
doi: 10.1161/CIRCULATIONAHA.120.046761
pmc: PMC7846288
doi:
Substances chimiques
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
0
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
449-465Subventions
Organisme : Medical Research Council
ID : MR/S005382/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : AA/18/2/34218
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/12/3/29423
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/16/1/32013
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/17/10/32859
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/19/33/34385
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0700320
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/12/3/29609
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/07/003/23133
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/11/15/29375
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/10/75/28537
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/12/5/29576
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R01065X/2
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/17/44/33064
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K01577X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P023150/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/17/6/32944
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 0998981Z/12/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/16/66/32288
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/16/12/32451
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/15/9/31534
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/17/17/32438
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R01065X/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/15/5/31110
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P023150/2
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/17/16/33294
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
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